Tarafa G, Villanueva A, Farré L, Rodríguez J, Musulén E, Reyes G, Seminago R, Olmedo E, Paules A B, Peinado M A, Bachs O, Capellá G
Laboratori D'Investigació Gastrointestinal, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Oncogene. 2000 Jan 27;19(4):546-55. doi: 10.1038/sj.onc.1203353.
Chromosome 18q is lost a high proportion of colorectal and pancreatic cancers. Three candidate tumor suppressor genes, DCC, Smad4 and Smad2 have been identified in this chromosome region. DCC and Smad4 aberrations have been previously identified in pancreatic and colorectal tumors. The aim of this study was to compare the presence of concurrent genetic aberrations in DCC and neighboring Smad4 and Smad2 genes during colorectal and pancreatic distal dissemination. We have used a panel of orthotopically implanted colorectal and pancreatic xenografts and corresponding metastases. We have shown that while LOH at DCC locus occurred at a similar frequency in both tumors, diminished DCC protein expression was exclusively present in colorectal tumors harboring intragenic DCC LOH. In contrast, in pancreatic xenografts loss of DCC protein and mRNA expression was restricted to metastases. Smad4 gene aberrations were detected at a similar frequency in both tumors and were selected for during distal dissemination. Acquisition of alterations in both genes occurred independently. Our results suggest that both DCC and Smad4 contribute to pancreatic and colorectal distal dissemination. However, the role of DCC may differ between both tumor types.
18号染色体长臂在相当一部分结直肠癌和胰腺癌中缺失。在该染色体区域已鉴定出三个候选肿瘤抑制基因，即DCC、Smad4和Smad2。先前在胰腺和结直肠肿瘤中已鉴定出DCC和Smad4异常。本研究的目的是比较在结直肠癌和胰腺癌远端播散过程中，DCC以及相邻的Smad4和Smad2基因同时发生基因异常的情况。我们使用了一组原位植入的结直肠癌和胰腺癌异种移植瘤及其相应的转移灶。我们发现，虽然DCC基因座的杂合性缺失（LOH）在两种肿瘤中出现的频率相似，但DCC蛋白表达降低仅出现在具有基因内DCC LOH的结直肠癌中。相反，在胰腺癌异种移植瘤中，DCC蛋白和mRNA表达的缺失仅限于转移灶。在两种肿瘤中检测到Smad4基因异常的频率相似，并且在远端播散过程中被选择。两个基因改变的获得是独立发生的。我们的结果表明，DCC和Smad4都参与了胰腺癌和结直肠癌的远端播散。然而，DCC在两种肿瘤类型中的作用可能有所不同。
